1. Office of Hematology and Oncology Products
Ann T. Farrell, M.D.
Division Director
Division of Hematology Products
Office of Hematology and Oncology Products
Center for Drug Evaluation and Research

2. Disclosure
I have nothing to disclose and will not discuss off-label uses.

3. FDA Mission
protect the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices.
responsible for the safety and security of most of our nation’s food supply, all cosmetics, dietary supplements and products that give off radiation.
responsible for regulating tobacco products

4. FDA Structure Center for Drug Evaluation and Research (CDER)
Regulate Drugs and Biologics except for vaccines, blood and plasma products and cellular based therapies – 16 review divisions
Center for Biologic Evaluation and Research (CBER)
Cellular therapies - Office of Cellular, Tissue and Gene Therapy
Vaccines – Office of Vaccines
Blood and Plasma Products – Office of Blood Research and Review

5. Four Main Areas that Impact Public
Determine whether protocols submitted under an investigational new drug (IND) application are safe to proceed
Approve Drugs/Biological Products for widespread commercial marketing
Work with Pharmaceutical Manufacturers to manage production and safety issues that arise
Permit access to drugs or biological products in development for compassionate use

6. FDA and You Patient Advisors – Special Government Employees
Consultation
Advisory Committee Meetings -- ODAC
Patient Focused Drug Development Meetings – 5th authorization of Prescription Drug User Fee Act/Food Drug Administration Safety and Innovation Act (July 9, 2012) – 5 years (lung cancer – July 2013, sickle cell disease – February 2014)
CDER’s Center Director Office – Professional Affairs and Stakeholder Engagement
Federal Register Notice – 11/4/14 – wants suggestions
Professional Affairs and Stakeholder Engagement -a focal point for advocacy, to enhance two-way communication and collaboration with healthcare professionals, patients, patient groups, and others on CDER issues concerning drug development, drug review, and drug safety.

7. Division Structure Divisions organized by area of expertise
Project Manager (PM) coordinates multidisciplinary teams
Discipline-specific teams
Primary and secondary review
Within the Center for Drug Evaluation and Research, there are 16 different divisions which are organized by areas of expertise. The RHPM or CSO coordinates a multidisciplinary team. Discipline specific teams exist with a primary reviewer and a team leader who performs primary and secondary reviews respectively.

8. Staff with Significant Expertise
Reviewers are Clinicians – Medical Officers, Physician Assistants, Nurse Practitioners
Chemists, Biologists, Microbiologists
Pharmacologists/Toxicologists
Clinical Pharmacologists
Statisticians
Epidemiologists
Social Scientists, Ethicists
Regulatory Expertise - Lawyers, Project Managers
External Advisors (Special Government Employees)

9. Drug Development Timeline
End of
Phase I
Meeting
End of
Phase II
Meeting
IND
Submission
Clinical
Start
Pre-NDA
Meeting
NDA/BLA
IND Review
Annual reports
IND Amendments
30 days
Clinical
hold
Phase I
Phase II
Phase III

10. Orderly and Logical Progression of Studies
Lab studies first, then animal, then human
Small studies before large
Short studies before long
Low dose before high dose
Each step builds on prior experience
As outlined on the slide, drug development is an orderly process. The process starts with lab studies and then progresses into animal studies and then clinical humans trials.
In general
Small studies before large
Short studies before long
Low dose before high dose
Each step builds on prior experience

11. Oncology Drug Development
Lab studies first, then animal, then human
Small studies before large ones
Phase 1 (dose escalation accelerated titration 1 by 1 or 3 plus 3)
Phase 2 (sometimes main trial for accelerated approval)
Available therapy
Unmet need
Risk/benefit
Phase 3 (usually one trial – pivotal trial)
Each step builds on prior experience
Phase 4 studies post-approval to address safety/efficacy issues

12. Investigational New Drug (IND)
Determine whether protocols submitted under an investigational new drug (IND) application are safe to proceed
Research (physician working at a university/center)
Commercial (Pharmaceutical Sponsors or other)
Expanded Access
Intermediate protocol
Single Patient
Emergency

13. IND Formal application to the Agency to conduct research
Requirements for submission
FDA has 30 days to get back to the sponsor regarding whether the trial is safe to proceed or not
Team reviews
Deficiencies – notify the sponsor and recommend how to correct them
If not corrected --- clinical hold

14. INDs Fast Track Designation – nonclinical data
Break Through Designation – clinical data
Focused attention on the development program

15. Basis for NDA and BLA Approval
Demonstration of efficacy with acceptable safety in adequate and well-controlled studies
Ability to generate product labeling that
Defines an appropriate patient population for treatment with the drug
Provides adequate information to enable safe and effective use of the drug
So when we approve a drug or biologic product, we generally have sufficient information from adequate and well-controlled studies to generate product labeling. The product labeling must define the patient population for whom the treatment is used and adequate information to enable safe and effective use. I am going to stress a couple of points here:
we have to be able to describe for whom the treatment should be prescribed and that is guided by the data submitted for review because in general the study population is what goes into the description
we have to be able to describe a dosing regimen, what the expected benefits and what the expected risks are

16. Requirements for Drug Approval
Safety (FDAC 1938)
Efficacy established in adequate and well-controlled investigations (FDAC 1962)
Use of data from one trial plus supportive evidence (FDAMA 1997)

17. Approval Accelerated or Regular Regular Approval Accelerated Approval
Based on clinical benefit
Accelerated Approval
Affect a surrogate endpoint other than mortality or irreversible morbidity
Surrogate endpoint must be reasonably likely to predict clinical benefit, based on epidemiologic, therapeutic, pathophysiologic, or other evidence
Additional studies confirming clinical benefit must be completed after approval

18. Clinical Benefit Improvement in survival
Improvement how a patient feels
Improved functioning
Clinical benefit must be demonstrated to receive regular approval. Clinical benefit is defined as prolonged patient survival or an improvement in how a patient feels or functions.
Cancer and hematologic conditions often cause symptoms that lead to patient suffering. Improvement in symptoms of cancer, properly measured, using an instrument that is ‘fit for purpose’ in the intended patient population, could provide evidence of clinical benefit and support a regular approval.
A symptom endpoint may support a claim of treatment benefit if it is used as a primary or secondary endpoint in adequate and well-controlled oncology or hematology clinical trials and if the studies also demonstrate a favorable treatment effect on the disease.
The Office of Hematology and Oncology Products works with Sponsors to incorporate Clinical Outcome Assessments into their drug development plans when appropriate. 18 18

19. Accelerated Approval Serious and life-threatening illness
New therapy must provide advantage over available therapy
ability to treat patients unresponsive to or intolerant of
improved patient response

20. Evidence for Accelerated Approval
Substantial evidence from well-controlled clinical trials regarding a surrogate endpoint
NOT: Borderline evidence regarding a clinical benefit endpoint

21. Greatest Potential for Problems
Chemistry, Manufacturing and Control
Efficacy Data
Safety Data
Clinical Data goes to an Oncologics Drug Advisory Committee (AC) Meeting or other AC
Meet several times a year to discuss scientific issues

22. How many trials? Usually more than one trial is needed.
Substantial evidence: “Adequate and well-controlled investigations”
Sometimes a single trial may suffice.
FDAMA (1997) single trial plus other supportive evidence
1998 FDA Effectiveness Guidance:
Statistically strong evidence
Multicenter trial
Important clinical benefit
Additional trials not ethical

23. Review Time Standard 10 months plus 2 months
Priority 6 months plus 2 months
Expedited less than 6 months (usually)

24. Oncologic Drugs Advisory Committee Meetings
November – Panobinostat and Triferic Applications
September 2013 – Perjeta in combination with trastuzumab/docetaxel demonstrating neoadjuvant pathologic CR
May 2013 – Animal data for approval of agents to treat radiation-induced myelosuppression associated with a radiological/nuclear incident
November 2011 – Facilitating anticoagulant drug development in pediatrics

25. 2014 NME Recent Approvals Cyramza (ramucirumab) – gastric cancer
Sylvant (siltuximab) – multicentric Castleman’s disease
Zykadia – non-small cell lung cancer
Belodaq (bellinostat) – peripheral t-cell lymphoma
Zydelig – CLL, Follicular B-cell non-Hodgkins Lymphoma, small cell lymphocytic lymphoma
Keytruda – melanoma

26. Permit access
Permit access to drugs or biological products in development for compassionate use
widespread – commercial marketing
not marketed – emergency INDs, Single Patient INDs
physician working with a pharmaceutical sponsor
process which includes providing documentation, letters, etc.

27. Risk/Benefit

28. Ponatinib- original indications
kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy
The indication on this slide is for the original approval of Iclusig. There is no test specified here because the requirement for a test was not considered necessary for the product to be used. Although much of the development was for patients whose disease had the T315I mutation, there was data showing a similar response rate for those without the mutation.

29. Ponatinib original approval
Efficacy (MCyR) for CML
Relapsed CML – 49%
CML with T315I -70%
Accelerated Phase CML (CHR) – 47%
Blast Phase CML (CHR) – 21%
Ph+ Acute Lymphoblastic Leukemia – 34%
Safety
Arterial thrombosis – 8% (MI, Stroke, gangrene)

30. Ponatinib approval
October 2013 – voluntarily withdrawn from market available via expanded access protocol
December 2013 – returns to market
Efficacy – unchanged
Safety –
Changed Box Warning to reflect
Increase in Vascular Occlusive Events – 27%
New warning for Heart Failure

31. Ponatinib – latest indications
Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315Ipositive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
The Agency takes its post-marketing surveillance seriously, and after the percentage of adverse events appeared to triple in a short time frame, we felt it best to restrict the drug for those patients who truly needed it. Those who were T315I positive or those who had no other options. The decision on whether it was absolutely necessary for a test can be summed up this way – you can get here either by multiple trials with various approved TKIS or get mutation testing done in either instance you would be a candidate for this product. So the indication was felt to be low risk from a CDRH perspective for a companion diagnostic.

32. References